DESCRIPTION (applicant's abstract): The Ly-6 super family of proteins has common structural cysteine motifs and is GPI anchored to the cell surface. The functions associated with them include cell:cell adhesion, regulation of responses to cytokines, complement inhibition and cell activation perhaps resulting from interactions with ligands and adjacent cell surface receptors. The Ly-6 antigens are expressed on distinct cell populations and thus transcriptional regulation is an important factor determining their expression patterns. Cytokines, especially IFNs, can significantly alter the expression of Ly-6 in a cell type specific manner. The objective of these studies is to define the function of the subset of Ly-6 antigens that are associated with hematopoietic lineages and assess what contribution they may have on the differentiation process of these lineages. The specific aims of the proposal are: (1) to identify the ligand(s) for Ly-6 antigens; (2) to characterize the relationship of Ly-6 antigen expression with the development of distinct hematopoietic lineages using Pax5-/- cells; (3) to characterize the effects of the Ly-6 signaling pathway on effector function and cell cycle regulation in Th2, Th1 and CD8 T cells; (4) to further characterize tissue specific transcriptional regulation of Ly-6A/E and characterize additional novel family members and (5) to generate and characterize the phenotype of Ly-6C and Ly-6I knockout mice. We have observed that Ly-6I together with Ly-6AIE, Ly-6C or Ly-6G may define distinct cell populations and we will determine whether Ly-6I can be used to further define hematopoietic stem cells.